Molecular Mechanisms Controlling Foxp3 Expression in Health and Autoimmunity: From Epigenetic to Post-translational Regulation.

Alessandra Colamatteo,Veronica De Rosa,Paola De Candia,Francesca Di Rella,Giorgia Teresa Maniscalco,Clorinda Fusco,Mario Galgani,Fortunata Carbone,Sara Bruzzaniti

doi:10.3389/fimmu.2019.03136

Abstract

The discovery of the transcription factor Forkhead box-p3 (Foxp3) has shed fundamental insights into the understanding of the molecular determinants leading to generation and maintenance of T regulatory (Treg) cells, a cell population with a key immunoregulatory role. Work over the past few years has shown that fine-tuned transcriptional and epigenetic events are required to ensure stable expression of Foxp3 in Treg cells. The equilibrium between phenotypic plasticity and stability of Treg cells is controlled at the molecular level by networks of transcription factors that bind regulatory sequences, such as enhancers and promoters, to regulate Foxp3 expression. Recent reports have suggested that specific modifications of DNA and histones are required for the establishment of the chromatin structure in conventional CD4+ T (Tconv) cells for their future differentiation into the Treg cell lineage. In this review, we discuss the molecular events that control Foxp3 gene expression and address the associated alterations observed in human diseases. Also, we explore how Foxp3 influences the gene expression programs in Treg cells and how unique properties of Treg cell subsets are defined by other transcription factors.

Highlights

The key evidence of Forkhead box-p3 (Foxp3) as regulatory T (Treg) cell lineage-specific transcription factor is that its gene mutations lead to autoimmune disease in both mice and humans [1, 2]
While Foxp3 can drive T regulatory (Treg) cell development and function by establishing the required cell program, gene expression analysis of Foxp3+ and Foxp3− T cells suggests that many Treg cell-specific genes are independent of Foxp3, changing the paradigm of Foxp3 as the only factor required for the establishment of Treg cell phenotype [10, 11]
Foxp3 phosphorylation is mediated by the kinase PIM2 that physically interacts with Foxp3 and phosphorylates multiple sites in the N-terminal domain, inhibiting Treg cell stability and suppressive function [Figure 2; [146]]. These findings indicate that regulation of Foxp3 expression and the subsequent Treg cell function rely on several molecular processes; pharmacological manipulation of these pathways may open the way for novel immunological tools to control Treg cell function and immunological tolerance in immunerelated disorders

Summary

Introduction

The key evidence of Forkhead box-p3 (Foxp3) as regulatory T (Treg) cell lineage-specific transcription factor is that its gene mutations lead to autoimmune disease in both mice and humans [1, 2]. CNS0 is bound by the special AT-rich sequence binding protein (Satb)1, a transcription factor that functions as a chromatin organizer, whose expression precedes Foxp3 protein appearance in Treg cell precursors, and whose deletion reduces Foxp3 expression and tTreg cell development [Figure 1; [73]].

Results

Conclusion